Pulmonary drug delivery represents a new drug administration method that provides many advantages. It provides direct and fast topical treatments for respiratory and lung diseases. It avoids the first-pass GI (gastrointestinal) metabolism and can provide targeted delivery to heart and brain. Large molecules such as peptides and proteins can be systemically delivered using the pulmonary channel. Pulmonary drug delivery also allows the use of drugs with low solubility. Most peptide and protein drugs are far more stable in the solid rather than liquid state. Antibiotics and even vaccines can be delivered in this manner. Compared to oral in-take, it provides a fast and much more efficient adsorption. Typically, only a few percent of the medication of the oral in-take is required for pulmonary delivery due to that many drugs degrade in the digestive tract before they are absorbed. Compared to intravenous injection, it provides a painless and safer alternative.
Numerous methods can be employed to generate drug aerosols in therapeutically useful size ranges and concentrations [A. J. Hickey, Inhalation Aerosols: Physical and Biological Basis for Therapy, New York, 1996]. Specifically, these are metered-dose inhalers (MDIs), dry powder inhalers (DPIs), and nebulizers, that can achieve minimally acceptable characteristics in simple, convenient, inexpensive, and portable format.
Nebulizers such as jet nebulizers or ultrasonic nebulizers are used for the delivery of aqueous pharmaceuticals and are generally large in design and complex to operate, so that they are more for clinical use. The precision of the dose administered to the patient is highly dependent on a variety of factors such as atmospheric temperature and humidity, as well as the volume and strength of the patient's breathing. Metered Dose Inhalers (MDI) suspends or dissolves the ultra-fine drug powders into liquid propellants and stores them. When a metered quantity of the propellant is released from the storage canister, the propellant evaporates and expands quickly to disperse the powdered drug or liquid droplet drug into the patients' mouth. The propellant can be a chlorofluorocarbon, a hydrochlorofluorocarbon, or a hydrocarbon, some of which are unfavourable due to environmental concerns. The another key problem with this method is that the quick expansion of the propellant causes the drug to impact in the back of the throat, reducing the amount being inhaled into the lung to about 20-30% [Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Product, U.S. Department of Health and Human Services, 1998]. More recent developments with improvement in design, such as the new SoftMist inhaler, has claimed a high FPF (fraction of fine particles), which suggests a higher lung deposition rate [M. W. Spallek, J. Geser, H. Reincke, and A. Moser, Scale-up and production challenges of bringing Respimat SoftMist inhaler (SMI) to market, Respiratory Drug Delivery IX, 2004, and R. Dalby, M. W. Spallek, and T. Voshaar, A review of development of Respimat SoftMist Inhaler, Int. J. Pharmaceutics, 2003]. In general, however, the MDI method needs good breath coordination and it is difficult to predict the amount of drug inhaled if the patients' inhalation does not coincide with the drug releasing.
Dry powder inhaler (DPI) is similar to a metered dose inhaler in that it also delivers a precisely measured dose medicine into the lungs, but in dry powder form. It is designed to generate a drug powder aerosol onto or via the inspiratory air flow. It has been proved that powder aerosols can carry approximately five times more drug in a single breath than metered dose inhaler (MDI) systems and many more times than liquid or nebulizer systems.
To facilitate pulmonary delivery, drug powders should normally be less than 5 μm (or equivalent aerodynamic diameter) so that they become airborne during inhalation. However, powders of such small sizes (typical group C powder in the Geldart classification) [D. Geldart, Types of Gas Fluidization, Powder Technology, Vol. 7, 285-297, 1973] have very strong inter-particle forces that make them agglomerate and very difficult to handle. The agglomeration of powder is normally formed prior to delivery due to the inter-particle forces, and possible moisture absorption. Agglomerated drug powders become difficult to dispense completely from the doses, and/or, is dispensed at least partially as larger agglomerates, thereby significantly reducing the lung deposition efficiency.
To overcome the inter-particle forces, current industrial practice applies two different methods; one is the suspension of the powder into liquid in Metered Dose Inhalers (MDIs) as described above, and the other involves mixing the ultra-fine drug powders with large amounts of coarser powder. This method uses a large quantity of excipient (filler) particles that are much larger (normally group A or group A-C powders in the Geldart classification). This makes the small-large powder mixture fluidize easily so that they can be handled easily. It also significantly increases the volume of each dosage so that the dispensing and packing becomes more accurate relatively. This is practiced for most dry powder inhaler (DPI) currently on the market. However, only a small fraction of the small drug particles can detach effectively from the large excipient particles during inhalation and the rest stay with the large particles and land in the mouth. This limits the efficiency of final delivery for DPIs to about 6-14%. [I. J. Smith, M. Parry-Billings, The Inhalers of the Future? A Review of Dry Powder devices on the Market Today, Pulmonary Pharmacology & Therapeutics 16, 79-95, 2003].
The current designs of dry powder inhalers (DPIs) can be divided into two types, the pre-metered and the device-metered ones [Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Product, U.S. Department of Health and Human Services, 1998] both of which can be driven by patient inspiration alone (Passive dry powder inhaler) or with some power-assistance (Active dry powder inhaler) [Guidance for Industry: Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Product, U.S. Department of Health and Human Services, 1998] Pre-metered DPIs contain previously measured doses in single or multiple presentations in blisters, capsules, or other cavities that are subsequently inserted into the device during manufacture or by the patient before use. Thereafter, the dose may be inhaled directly from the unit or it may be transferred to a chamber before being inhaled by the patient. Device-metered DPIs have an internal reservoir containing sufficient formulation for multiple doses being metered by the device itself during actuation by the patient.
Passive dry powder inhalers rely on the aspiratory flow as the sole source of energy for powder fluidization, deagglomeration and inhalation. A number of such inhalers have been developed. These include the Ultrahaler (Aventis), the Clichhaler (Asmabec), Turbuhaler (Astra), and Diskus (GlaxoSmithKline) [I. J. Smith, M. Parry-Billings, The Inhalers of the Future? A Review of Dry Powder devices on the Market Today, Pulmonary Pharmacology & Therapeutics 16, 79-95, 2003 and C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols, KONA, 16, 7-45, 1998].
The AstraZeneca Turbulhaler is a multiple dose inhaler with 50, 100 or 200 doses of active drug stored in a reservoir [U.S. Pat. No. 6,257,732, U.S. Pat. No. 6,325,061,1. J. Smith, M. Parry-Billings, The Inhalers of the Future? A Review of Dry Powder devices on the Market Today, Pulmonary Pharmacology & Therapeutics 16, 79-95, 2003 and C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols, KONA, 16, 7-45, 1998]. The drug is metered into small doses by scrapers inside the inhaler. Air enters the inhaler and passes through the dosing unit, fluidizing the powder by shear force. The turbulence in the narrow inhalation channel, the impaction on the bottom of the mouthpiece, and high shear stress in the swirl nozzle of the mouthpiece help the particle deagglomateration. In this inhaler, it includes two metering and inhalation processes. It is unique in dispensing minute quantity of drug powders without the use of an added carrier.
The Diskus [I. J. Smith, M. Parry-Billings, The Inhalers of the Future? A Review of Dry Powder devices on the Market Today, Pulmonary Pharmacology & Therapeutics 16, 79-95, 2003 and C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols, KONA, 16, 7-45, 1998] is a blister pack, unit-dose device. The pack consists of a coiled, double-foil strip of 60 blisters, each containing one dose of drug powder with a lactose carrier. The drug can be in the 50-500 μg range. During inhalation, each blister is moved into place, and its lid-foil is peeled away by a contracting wheel. The inhaled air is drawn through the opened blister, aerosolizing and delivering the dose through the mouthpiece.
Clickhaler [C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols, KONA, 16, 7-45, 1998] consists of a metering cone, bulk drug reservoir, and compression spring. It holds 100 or 200 doses of drug. Only one metered dose is present in the inhalation passage at any one time. The inhaler should be held approximately upright during priming and inhalation, and a rapid and deep inhalation is needed for optimal dose delivery.
Active dry powder inhalers have an additional source of energy than that provided by inhalation to fluidize and disperse the powder. The Nektar Pulmonary Inhaler [U.S. Pat. No. 6,089,228] is a gas-assisted dry powder inhaler. It comprises a relatively large transparent holding chamber with a powder inlet at one end of the feed chamber. The powder inlet has a receptacle where a foiled dosage containing the medicament can be penetrated and a pressurization cylinder providing high pressure air stream extract the powdered medicament from the receptacle to the chamber and disperse in flowing compressed gas to form an aerosol. It is claimed that this kind of inhaler provides an efficient pulmonary delivery of accurate, precise, and repeatable dosages of powdered medicaments. A patient pulls a hand pump to compress a small charge of air, inserts a packet of drug powder into the slot, then presses the firing button to disperse the powder into an aerosol cloud The inhaler generates the aerosol independently of patient inspiratory flow rate, and it is Ideal for large and small molecules with 2-5 mg doses.
The SPIROS™ (Dura) has a breath activated, motor driven impeller which provides electromechanical energy to disperse the powder [C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols, KONA, 16, 7-45, 1998]. The Prohaler™ (Valois) is a multi-dose powder inhaler where a built-in pump gives compressed air to facilitate dose metering and powder dispersion [C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols, KONA, 16, 7-45, 1998].
The additional energy input decreases or eliminates the dependence of the aerosolization process on the patient's breathing ability, increases the fine particle fraction in aerosol flow and ensures effective powder dispersion [C. A. Dunbar, A. J. Hickey and P. Holzner, Dispersion and Characterization of Pharmaceutical Dry Powder Aerosols, KONA, 16, 7-45, 1998]. However, these kinds of inhalers can be big and heavy, are not very convenient for patient use, and also its cost can be much higher than desired. Additionally, breath coordination becomes very important for the active DPIs in most cases, as patient inhalation and aerosolization needs to be synchronized.
Currently, the most popular formulation of powder for DPIs consists of the drug that is usually blended with a carrier (lactose or glucose) to facilitate flow and dispersion. The suitability of a carrier is dependent on its chemical and physical characteristics, which can have direct effect on the performance of the product such as ease of entrainment of the formulation, energy input necessary for dispersion and aerosolization of the active ingredient from the carrier. It would be ideal if the required small quantity of the fine drug powder could be accurately dispensed alone, without any carrier/incipient. When only the pure drug powder is packaged into the inhaler, if the particle aggregates can be dispersed into primary particles (<5 μm), the delivery efficiency is expected to increase significantly. Considering that many drugs are quite expensive, typically being many times more costly than conventional drugs, it is very critical to be able to efficiently deliver the dry powders to the target region of the lung with minimal loss of the drug.
There are various types of inhalers for delivering a dry powdered medicament. For example, U.S. Pat. No. 6,116,239 discloses an inhalation device for use in delivering a powdered substance to a user. It comprises a holding portion for holding the powder substance, an air entry passageway having an inlet port open to an exterior of the device to direct air entering it and to fluidize the medicament upon inhalation by the user. A hold-up chamber is for holding the fluidized medicament and maintaining the substance in a fluidized state, then to deliver them to the user through an air exit passageway. The hold-up chamber is cylindrically shaped and has a longitudinally extending axis around which air is inhaled. The powder substance is claimed to be effectively deaggregated almost immediately upon inhalation and form a relatively uniform concentration of powder.
U.S. Pat. No. 5,975,076 discloses a dry powder inhaler which comprises a reservoir of medicament powder, a dispensing chamber for receiving a charge of powder to be dispensed, an air passage having an inlet terminating at a nozzle directed downwardly into the dispensing chamber. Air is drawn in through the inlet to enter the dispensing chamber as a jet through the nozzle in a direction which is both downwardly onto the medicament and laterally across the chamber with respect to the mouthpiece.
U.S. Pat. No. 5,921,237 describes a drug powder inhaler including a cover plate pivotally attached to a lid on the inhaler housing. A blister pack disk is rotatably mounted on the housing under the cover plate. An actuator in the housing is most desirably aligned with a lever on the cover plate. When a patient pushes the actuator, it presses to shear open a blister on the blister pack disk and delivers the drug in the dose in the blister into a staging chamber for inhalation by the user.
In U.S. Pat. No. 6,006,747, a dry powder inhaler has a multi-dosage medicine containing cartridge attached on the top of the housing, and a cartridge ring with apertures for holding dry powder medicine. The housing includes a mixing or aerosolizing chamber. A pressure switch is located in the housing for actuating the mixing process within the chamber. A lid is pivotally attached to the housing and is used to index or advance the cartridge ring to a next aperture for delivery of successive drug dosages. During inhalation, a pressure differential develops across the venturi air passageway and reaches a predetermined level, then the motor is turned on by the pressure switch.
U.S. Pat. No. 6,055,980 describes a dry powder inhaler comprising: a housing, a mixing chamber in the housing, an impeller within the space of the mixing chamber, a motor linked to the impeller, at least one inlet opening leading into the mixing chamber, and at least one outlet opening leading out of the mixing chamber. The device uses breath-actuation and is generally independent of patient coordination. A motor spins the impeller at high speed. A plunger introduces a dose of powdered medicine into the chamber so that all powder particles are available for intermixing disaggregation and comminution. The drug-laden air flows out of the chamber and into a mouthpiece. It provides a proper mixing of air and powdered drug particles for inhalation by a patient.
U.S. Pat. No. 6,209,538 describes an inhalation-activated dry powder inhaler, that has a primary inhalation passage extending through the housing, and a secondary inhalation passage disposed in communication with the primary inhalation passage and a source of medicament. As the user's inhalation reaches a defined rate, the flow inhibiting mechanism restricts flow through the primary inhalation passage and moves the blocking plate to enable airflow through the secondary passage. The medicament is provided through the secondary inhalation passage, thereby optimizing the delivery of medicament to the lungs.
Most of these dry powder inhalers are ideal for large amount medicament delivery (with 2-5 mg per dose). The formulation of the powder used is usually blended with large particle carriers. There are several problems related to delivery of small quantity of dry powder pharmaceuticals with these inhalers. First, these inhalers all apply an air entry passageway and an air exit passageway on the same side of blister or cartridge. The powder is extracted from its receptacle only by shear force. When the drug receptacle becomes too small drug powder is too cohesive, it becomes difficult to draw entire dry powder completely out from the receptacle and break up the particle aggregates. This will reduce the efficiency of the delivery. Secondly, these devices usually achieve delivery of fine drug particles by a two-step dispersion. It uses a chamber for receiving and maintaining the fluidized drug powder then deliver them to the user. This will cause some waste of expensive drug powder and decrease the accuracy of delivery due to the fine powder stuck on the surface of the chamber. Furthermore, some of the delivery devices are large or expensive, and inconvenient for changing for different medicaments and different dosage sizes.
There is therefore a need for an inhaler that is capable of accurately delivering small precise amounts of expensive powder drugs with minimal powder handling, in a compact and inexpensive instrument which does not require the need for excipients.